Peptides in which the xe2x80x94CONHxe2x80x94 linkage has been replaced by the xe2x80x94COCH2xe2x80x94 isosteric moiety are known as ketomethylene pseudopeptides1 having known utility. For example, such ketomethylene pseudopeptides may be useful as antibiotics, antibiotic enhancers or enzyme inhibitors. Further, this structural modification has been used to make peptide-like molecules with improved metabolic stability.2 This structural motif has been employed for the preparation of numerous enzyme inhibitors,3 and has even been found as a natural product.4 There have been a number of ingenious methods developed for the preparation of this important class of compounds. By far the most common approach to the synthesis of this class of peptide isosteres is to ignore the issue of absolute stereochemistry. There are reports of possible solutions to the question of the absolute configuration of the N-terninal optically active center.6 There is a singular report of a successful approach to the preparation of ketomethylene pseudopeptides with absolute stereocontrol at both asymmetric centers.7 
Inhibitor molecules based on the ketomethylene isostere have been found to be potent inhibitors of ACE (angiotensin converting enzyme),2 Substance P,3b carboxypeptidase A,3c carboxypeptidase A,3c and HIV protease.8 
The preparation of optically active alpha-amino ketones by dehydrogenation of racemic alpha-amino ketones and hydrogenation using an asymmetric hydrogenation catalyst is disclosed for dehydroketomethylene pseudopeptides having an aromatic substituent adjacent the keto group in U.S. Pat. No. 4,277,420; East German Application Nos. 280,527; 280,528; 280,529; 240,372 described in corresponding Derwent Abstract Numbers 90-362220/49, 90-362221/49, 90-362222/49, 87-057083/09, respectively.
Additional references directed to optically pure optically active intermediates include:
U.S. Pat. No. 4,912,221;
EP Application No. 90307750.1;
U.S. Pat. No. 4,906,773;
U.S. Pat. No. 4,916,252;
U.S. Pat. No. 4,316,847;
EP Application No. 89403599.7;
Japanese Number 3002152A described in WPI Acc No. 91-048825;
German Appl. No. 140-036 described in Derwent Abstract No. 34661C/20.
Disclosure for a rhodium di (1R, 2R)- or (1S, 2S)-bis(phenyl-4-methoxyphenylphosphino)ethane (Rh DiPAMP) catalyst and its use as an enantioselective hydrogenation catalyst is exemplified in each of the following:
J. Am. Chem. Soc. 1977(August 31), 99;17 pp. 594652;
J. Am. Chem. Soc. 1977(September 6), 94:18 pp. 6429-33;
Synthesis 1979(May) pp. 350-2; and
Chem. Ber. 1981, 114, pp. 1137-49.
The present process takes advantage of the very practical method for the preparation of optically active succinates9 as a key component for a modified Dakin-West reaction. This protocol effectively introduces the C-terminal optically active center with the appropriate D- or L-amino acid absolute configuration at C-2. The Dakin-West reaction does not however offer a method for the control of the N-terminal optically active center at C-5. In an effort to control both asymmetric centers of a ketomethylene pseudopeptide, the present invention provides a method for the dehydrogenation/asymmetric hydrogenation of certain ketomethylene pseudopeptides. The invention is a novel synthetic method for the preparation of this class of peptide isostere in which both asymmetric centers are fixed with known absolute configuration. The present method permits the introduction of the C-5 optically active center with very high optical purity. In addition, since the absolute configuration of the C-5 center is induced by the absolute configuration of the asymmetric catalyst ligand, it is possible to make either optical antipode independently by the appropriate choice of ligand absolute configuration.
The flexibility of our synthesis permits the synthesis of very unique analogues of xcex1-amino ketones that have improved biological properties relative to molecules available by more demanding syntheses. The literature is replete with examples of novel amino acid side chains designed to impart improved biological properties to these molecules.
The present invention is a novel compound of the formula (I or I1) 
wherein
R1 is hydrogen, alkyl, lower cycloalkyl, or Ar wherein Ar is an aromatic group, preferably CH2Ar, including, particularly, unsubstituted or substituted phenylmethyl;
R2 is CH2R9 wherein N is
(a) hydrogen,
(b) C1-C4 alkyl optionally substituted with one or more hydroxyl, C1-C3 alkoxy, chloro, or fluoro,
(c) phenyl optionally substituted with one to three of C1-C4 alkyl, halogen where halogen is fluoro, chloro, bromo or iodo, hydroxyl, nitro, C1-C3 alkoxy, or xe2x80x94COxe2x80x94N(R7)2 wherein R7 is, independently, H or C1-C4 alkyl,
(d) a 5-7 member heterocycle such as pyridyl, furyl, indolyl or benzisoxazolyl,
(e) C3-C7 cycloalkyl, or
(f) naphthyl;
R3 is 
wherein one of R6 and R8 is hydrogen and the other is
(1) hydrogen;
(2) alkyl of from 1 to 6 carbons optionally substituted by one or two hydroxyl, chloro or fluoro;
(3) cycloalkyl of from 3 to 7 ring carbons;
(4) Ar4 which is a group such as phenyl, or phenyl substituted by one to three substituent(s) consisting of
(a) alkyl of from one to four carbons,
(b) halogen consisting of fluoro, chloro, bromo, iodo,
(c) alkoxy of from one to three carbons,
(d) nitro,
(e) amido,
(f) mono- or di-alkyl (of from one to four carbons)amido, or
(g) hydroxy;
(5) Ar5 which is tolyl;
(6) Ar6 which is tolyl substituted by one to three substituents consisting of
(a) alkyl of from of one to four carbons,
(b) halogen consisting of fluoro, chloro, bromo, iodo,
(c) alkoxy of from one to three carbons,
(d) nitro,
(e) amido,
(f) mono- or di-alkyl (of from one to four carbons) amido, or
(g) hydroxy;
(7) Ar7 which is a group optionally attached through a CH2 and is naphthyl or naphthyl substituted by one to three substituents consisting of
(a) alkyl of from one to four carbons,
(b) halogen consisting of fluoro, chloro, bromo, iodo,
(c) alkoxy of from one to three carbons,
(d) nitro,
(e) amido,
(f) mono- or di-alkyl (of from one to four carbons) amido, or
(g) hydroxy;
(8) Ar8 which is a group such as indol-3-yl, indol-2-yl, or imidazoly-4-yl or indol-3-ylmethyl, indol-2-ylmethyl or imidazol-4-ylmethyl (preferably unsubstituted or substituted phenyl or indol-3-yl);
(9) NHA wherein A is
(a) trityl,
(b) hydrogen,
(c) alkyl of from one to six carbons,
(d) R10CO wherein R10 is (A) hydrogen, (B) alkyl of from one to six carbons optionally substituted with hydroxyl, chloro, or fluoro, (C) phenyl or naphthyl; unsubstituted or substituted with one to three of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R11)2 wherein R11 is independently hydrogen or alkyl of from one to four carbons, or (D) a 5 to 7 member heterocycle such as indolyl, pyridyl, furyl or benzisoxazolyl;
(e) phthaloyl wherein the aromatic ring is optionally substituted by one to three of (A) alkyl of from one to three carbons, (B) halogen where halogen is F, Cl, Br, or I, (C) hydroxy, (D) nitro, (E) alkoxy of from one to three carbons, (F) CON(R11)2 wherein R11 is independently hydrogen or alkyl of from one to four carbons,
(f) R12(R13R14C)mCO wherein m is one to three and R12, R13, and R14 are independently (A) hydrogen, (B) chloro or fluoro, (C) alkyl of from one to three carbons optionally substituted by chloro, fluoro, or hydroxy, (D) hydroxy, (E) phenyl or naphthyl optionally substituted by one to three of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R11)2 wherein R11 is independently hydrogen or alkyl of from one to four carbons, (F) alkoxy of from one to three carbons, (G) 5 to 7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl, or (H) R12, R13 and R14 are independently joined to form a monocyclic, bicyclic, or tricycle ring system each ring of which is a cycloalkyl of from three to six carbons, except that only one of R12, R13 and R14 can be hydroxy or alkoxy on the same carbon and can not be hydroxy, chloro or fluoro when m is one;
(g) R12(R13R14C)mW wherein m is independently 1 to 3 and W is OCO or SO2 and R12, R13 and R14 are independently as defined above;
(h) R20W wherein R20 is a 5 to 7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl;
(i) R21W wherein R21 is phenyl or naphthyl unsubstituted or substituted by one to three substituents of (i) alkyl of from one to three carbons, (ii) halogen where halogen is F, Cl, Br, or I, (iii) hydroxy, (iv) nitro, (v) alkoxy of from one to three carbons, (vi) CON(R11)2 wherein R11 is independently hydrogen or alkyl of from one to four carbons;
(j) R12(R13R14C)mP(O) (OR22) wherein R22is alkyl of from one to four carbons or phenyl;
(k) R20P(O) (OR22) wherein R22 is as defined above;
(l) R21P(O) (OR22) wherein R22 is as defined above;
N(R11)2 wherein R11 is independently as defined above;
(10) R12(R13R14C)mV wherein V is O or NH and R12(R13R14 are independently as defined above;
(11) N(R11)2 wherein R11 is independently as defined above;
(12) NR15NR16 wherein R15 and R16 are joined to form a 4 to 6 membered saturated nitrogen containing heterocycle which is (a) azetidinyl, (b) pyrrolidinyl, (c) piperidinyl, or (d) morpholinyl;
(13) R17OCH2O wherein R17 is
(a) alkyl of from one to six carbons,
(b) R21 wherein R21 is independently defined as above; or
(c) CH2Q1 wherein Q1 is phenyl, naphthyl or a 5 to 7 membered heterocycle,;
(14) R17OCH2CH2OCH2 wherein R17 is independently as defined above;
(15) alkynyl of from two to six carbons optionally substituted with R21 where in R21 is independently as defined above;
(16) alkenyl of from two to six carbons optionally substituted with R21 where in R21 is independently as defined above;
R5 is independently hydrogen, alkyl, lower cycloalkyl, or an aromatic group, preferably unsubstituted or substituted phenyl;
R4 is hydrogen, an amino acid radical or a protecting group such as a substituted or unsubstituted acyl;
R5 is hydrogen, alkyl, lower cycloalkyl, or ar wherein ar is an aromatic group, preferably unsubstituted or substituted phenyl.
The present invention is also a process for the treatment of a compound of the formula (II or II1) 
wherein R1 and R2 is as defined above;
R3xe2x80x2 is 
wherein R6 is as defined above; and
R8xe2x80x2 is hydrogen, C1-C4 alkyl or cycloalkyl with the proviso that one of R6 or R8xe2x80x2 is hydrogen;
R4xe2x80x2 is a protecting group such as a substituted or unsubstituted acyl or amino acid radical;
R5xe2x80x2 is hydrogen;
with hydrogen in the presence of rhodium (R,R)-(1,2-ethanediyl bis[ortho-methoxyphenyl)phenylphosphine] (H2RhDiPAMP) in deoxygenated solvent;
optionally deprotecting the nitrogen or deprotecting the nitrogen and further treating to add an amino acid radical to the nitrogen to obtain a compound of the formula I or I1 wherein R1, R2, R3, R4, R5 and R6 are as defined above.
The present invention is a compound of the formula (II or II1) 
wherein R1, R2, R3xe2x80x2, R4xe2x80x2 and R5 are as defined above.
The present invention is also the preparation of compound of the formula II or II1 as defined above comprising the treatment of the compound of the formula (III or III1) 
wherein R1, R2, R3xe2x80x2, R4xe2x80x2 and R5xe2x80x2 are as defined above; with tertiary-butyl hypochlorite and 1,4-diazabicyclo[2.2.2]octane (DABCO) to obtain a compound of the formula II or II1.
C1-C3 or -C4 means alkyl of from one to three or four such as methyl, ethyl, propyl or butyl and isomers thereof and the like.
Protection of the amino group can be accomplished by methods well known to those familiar with amino acid chemistry. For example, the amino group be protected utilizing a carbonyl compound represented by the formula 
wherein Rxe2x80x2 represents alkyl radicals having from 1 to about 10 carbon atoms, and aryl, aralkyl and alkaryl radicals having from about 6 to about 26 carbon atoms; or aryl or alkylaryl or aralkyl with suitable carbon numbers, A represents oxygen; n is 0 or 1; and Q represents Cl, Br, I, or C(O)AnRxe2x80x2 wherein Rxe2x80x2, A and n have the same meanings as defined above. Exemplary amino protecting groups are acyl groups including such groups as acetyl, benzoyl, formyl, propionyl, butyryl, toluyl and may include substituted such groups, for example, nitrobenzoyl, and the like. In other words, the amino protecting groups are those commonly used as blocking groups in peptide synthesis.
C3-C7 cycloalkyl means cyclic hydrocarbon groups containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl cylopentyl, methyl cyclohexyl, dimethyl cyclopentyl, cycloheptyl and the like.
Ar is an aromatic group which means a phenyl, substituted phenyl, tolyl, substituted tolyl, naphthyl and the like.
Substituted phenyl and substituted tolyl means from one to three substituents such as alkyl, carboxyl, hydroxyl (and base salts thereof), alkoxy, halogen which means fluoro, chloro, bromo, or iodo, C1-C4 acyloxy, aryloxy, aralkoxy, amino, alkyl amido (both mono and di alkylamido), nitro, cyano.
Optically active means the compound includes at least one optically active carbon.
Generally, the process comprising the treatment of the compound of formula II or II1 with hydrogen in the presence of DiPAMP to obtain the compound of the formula I or I1 respectively is as set out hereinafter. The reaction is accomplished at from about 1 to 100 psig and at a temperature from about 0xc2x0 C. to 60xc2x0 C. preferably at about room temperature and at a pressure about 40 psig, in inert solvents such as methanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile and the like or mixtures thereof.
Evaluation of the results may be accomplished by standard methods, such as vapor phase chromatography on a optically active capillary column, or by HPLC (high performance liquid chromatography) on a optically active column or by evaluation of the optical rotation of a solution of the compound.
A Fisher-Porter bottle is charged with the appropriate substrate dissolved in deoxygenated methanol along with 0.1-1.0 mol percent rhodium (R, R)-DiPAMP (R,R)-(1,2-ethanediyl bis[(o-methoxyphenyl)phenylphosphine]. After 5 nitrogen purges (40 psig) the solution was purged 5 times with hydrogen (40 psig) and then allowed to hydrogenate at room temperature for 1-24 h. The hydrogen is replaced with nitrogen and the contents of the bottle concentrated in vacuo. The catalyst residue is separated from the optically active ketomethylene pseudopeptides I or I1 by dissolving the product in iso-octane. The catalyst residue is not soluble in iso-octane.
A general procedure for the hydrolysis of optically active N,O-protected ketomethylene pseudopeptides of the formula I or I1 wherein R4xe2x80x2 is a protecting group is as follows. A sample of the optically active N,O-protected ketomethylene pseudopeptide derivative is refluxed for 24 h with 12 N hydrochloric acid. The solvent is removed in vacuo. The residue is taken up in water and re-concentrated in vacuo. After thoroughly drying under vacuum the hydrochloride salt is converted to the free amine by treatment with excess propylene oxide. The precipitated amino acid is then isolated by filtration and optionally recrystallized from water/methanol.
An evaluation is made of optical purity by optically active vapor phase chromatography. The N,O-protected optically active ketomethylene pseudopeptide derivatives are analyzed by optically active gas chromatography for optical purity. A solution of the racemic ketomethylene pseudopeptide derivative in dichloromethane is separated into the two enantiomers by a 25 meter Chirasil Val III capillary column with flame ionization detection. After conditions for separation of the two enantiomers are established, each optically active hydrogenation product is evaluated for the extent of optical purity.
Generally, the compound of the formula II or II1 are prepared by the method shown in Scheme 2 hereinafter. 
The conditions of the treatment of formula III or III, by tertiary-butyl hypochlorite are at a temperature of 0xc2x0 C.-50xc2x0 C. in an inert solvent such as dichloromethane, chloroform, acetonitrile and the like The product of this treatment is then further treated with 1,4-diazabicyclo[2.2.2]octane (DABCO) at a temperature of 0xc2x0 C.-50xc2x0 C. in an inert solvent such as dichloromethane, tetrahydrofuran, chloroform, acetonitrile and the like.
Compounds of the formula III or III1 are prepared by methods known in the art or by methods analogous to those known in the art from starting material which are known or which can be prepared by known methods.
Variations in these conditions and evaluations for different compounds within the definitions of the formula I or I1 are within the skill of an ordinarily skilled artisan.
The general procedure for removal of a protecting group, such as the tert-butyl ester is as follows. A sample of the product, I and I1, is dissolved in dichloromethane and treated with an equal (volume) amount of trifluoroacetic acid at 0xc2x0 C. The solution is allowed to warm to room temperature and the progress of the reaction monitored by TLC. When the reaction is finished the solvents are removed in vacuo and the residue purified by crystallization or flash chromatography on silica gel.
The compounds of the Formula I or I1 are useful as intermediates in the preparation-of pharmacologically active compounds. It is contemplated that certain intermediates disclosed herein will manifest similar activity.
The compounds of Formula I or I1 which manifest pharmacologically active are useful both in the free base and the free acid form or in the form of base salts thereof, as well as, in the form of acid addition salts. All forms are within the scope of the invention. In practice, use of the salt form amounts to use of the free acid or free base form. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral and organic acids or those derived from bases such as suitable organic and inorganic bases. For example, see xe2x80x9cPharmaceutical Saltsxe2x80x9d, J. Pharm. Sci., 66(1), 1-19 (1977). The acid addition salts of said compounds are prepared either by dissolving the free base of compound I or I1 in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid or base and isolating the salt by evaporating the solution, or by reacting the free base of Compound I or I1 with an acid as well as reacting compound I or I1 having an acid group thereon with a base such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The base salts of compounds of Formula I or I1 described above are prepared by reacting the appropriate base with a stoichiometric equivalent of the acid compounds of Formula I or I1 to obtain pharmacologically acceptable base salts thereof.
Contemplated equivalents of the general formulas set forth above for the compounds I or I1 as well as the compounds useful to prepare compounds I or I1 are compounds otherwise corresponding thereto and having the same general properties wherein one or more of the various R groups are simple variations of the substituents as defined therein, e.g., wherein R2 or R3 is a higher alkyl group. In addition, where a substituent is designated as, or can be, a hydrogen, the exact chemical nature of a substituent which is other than hydrogen at that position is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.